An improved synthesis for the preparation of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide is described where methyl cyanoacetate is converted in eight operations or fewer to the desired product, as well as other valuable intermediates used in the process.
5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide is a valuable intermediate in the synthesis of Lipitor(copyright) (atorvastatin calcium) known by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate. The aforementioned compound is useful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and is thus useful as a hypolipidemic and/or hypocholesterolemic agent.
U.S. Pat. No. 4,681,893, which is herein incorporated by reference, discloses certain trans-6-[2-(3- or 4-carboxamido-substituted-pyrrol-1-yl)alkyl]-4-hydroxy-pyran-2-ones including trans (xc2x1)-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-](2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.
U.S. Pat. No. 5,273,995, which is herein incorporated by reference, discloses the enantiomer having the (R,R) form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N, 4-diphenyl-1-[(2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, i.e., [R-(R*,R*)]-2-(4-fluorophenyl)-xcex2,xcex4-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.
U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124.482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,998,633; and 6,087,511, which are herein incorporated by reference, disclose various processes and key intermediates for preparing atorvastatin.
Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat. Nos. 5,969,156 and 6,121,461 which are herein incorporated by reference.
A synthetic procedure for the preparation of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide is disclosed in U.S. Pat. No. 5,273,995.
The asymmetric reduction of xcex2-ketoesters, as well as xcex2-diketones, is a well-established transformation in organic synthesis. However, the complexity of these reactions increases in the case of 1,3,5-tricarbonyl systems and poor yields and poor stereoselectivities often result. In fact, investigations by Saburi (Tetrahedron, 1997, 1993;49) and Carpentier (Eur. J. Org. Chem. 1999;3421) have independently demonstrated low to moderate diastereo- and/or enantio-selectivities for diketoester asymmetric hydrogenations. Furthermore, the fact that the processes in the prior art require high pressure hydrogenation and extended reaction times makes these procedures impractical and not amenable to large-scale manufacturing processes.
However, we have surprisingly and unexpectedly found that the diol esters of the present invention, (R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid esters, can be obtained directly from the corresponding 1,3,5-tricarbonyl precursors in a highly stereoselective manner via a mild and efficient ruthenium-catalyzed asymmetric hydrogenation reaction utilizing chiral non-racemic diphosphine ligands in the presence of secondary activating agents such as protic acids.
The object of the present invention is a short and efficient process for the preparation of 5-(4-fluorophenyl)-1-[2-((2R,4R)4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide. The present process avoids the use of a costly chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction. Furthermore, a key Paal-Knorr condensation step, common to the present and prior art processes, has been improved through a significant decrease in reaction time.
Thus, the present process has significant advantages over the prior art processes and is amenable to large-scale synthesis.
Accordingly, the first aspect of the present invention is an improved process for the preparation of a compound of Formula (13) 
which comprises:
Step (a) reacting a compound of Formula (1) 
xe2x80x83wherein R is alkyl, aryl, arylalkyl, or heteroaryl in a solvent with a compound of Formula (2)
R1xe2x80x94Hxe2x80x83xe2x80x83(2)
xe2x80x83wherein R1 is xe2x80x94XR wherein
X is O,
S, or
Se, or R1 is 
xe2x80x83wherein R2 or R3 is independently
alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R2 and R3 together are
xe2x80x94(CH2)4xe2x80x94,
xe2x80x94(CH2)5xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)3xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)4xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)2xe2x80x94CH(R4))xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)3xe2x80x94CH(R4))xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH(R4)xe2x80x94
xe2x80x83wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N and R is as defined above to afford a compound of Formula (3) 
xe2x80x83wherein R1 is as defined above;
Step (b) reacting a compound of Formula (3) with hydrogen in the presence of a catalyst and a strong acid in a solvent to afford a compound of Formula (4) 
xe2x80x83wherein Y is Cl, Br, TsO, MsO, or HSO4, and R1 is as defined above;
Step (c) reacting a compound of Formula (4) with a base in a solvent followed by the addition of a compound of Formula (5)
Rxe2x80x94CO2Hxe2x80x83xe2x80x83(5)
xe2x80x83wherein R is as defined above in a solvent to afford a compound of Formula (6) 
xe2x80x83wherein R and R1 are as defined above;
Step (d) reacting a compound of Formula (6) with Compound (7) 
xe2x80x83in a solvent with removal of water to afford a compound of Formula (8) 
xe2x80x83wherein R1 is as defined above;
Step (e) reacting a compound of Formula (8) with a compound of Formula (9) 
xe2x80x83wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum and R1 is as defined above, in a solvent in the presence of a strong base to afford a compound of Formula (10) 
xe2x80x83wherein R1 is as defined above;
Step (f) reacting a compound of Formula (10) with hydrogen in the presence of a catalyst in a solvent in the presence of an acid to afford a compound of Formula (11) 
xe2x80x83wherein R1 is as defined above or a compound of Formula (11a) 
Step (g) reacting a compound of Formula (11b) 
xe2x80x83wherein R1a is OH, xe2x80x94XR wherein
X is O,
S, or
Se, or R1a is 
xe2x80x83wherein R2 or R3 is independently
alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R2 and R3 together are
xe2x80x94(CH2)4xe2x80x94,
xe2x80x94(CH2)5xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)3xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)4xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)2xe2x80x94CH(R4))xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)3xe2x80x94CH(R4))xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH(R4)xe2x80x94
xe2x80x83wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N, and R is as defined above in a solvent in the presence of an acid, followed by reaction with a base, an acylating agent, and an acylation catalyst in a solvent to afford a compound of Formula (12) 
Step (h) reacting a compound of Formula (12) with HOxe2x80x94M in an alcohol of Formula (17) or (17b)
HOCH2-Arylxe2x80x83xe2x80x83(17)
or HO-Allylxe2x80x83xe2x80x83(17b)
xe2x80x83wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum; or with a compound of Formula (16) or (16b)
M⊕xe2x8ax96OCH2-Arylxe2x80x83xe2x80x83(16)
or M⊕xe2x8ax96O-Allylxe2x80x83xe2x80x83(16b)
xe2x80x83wherein M is as defined above in an alcohol of Formula (17) or (17b) wherein aryl or allyl in a compound of Formula (16) or (16b) and (17) or (17b) is the same, in a solvent followed by the addition of hydrogen in the presence of a catalyst and an acid to afford the compound of Formula (13).
A second aspect of the present invention is an improved process for the preparation of a compound of Formula (8). 
wherein R1 is as defined above which comprises:
reacting a compound of Formula (4) 
xe2x80x83wherein Y is Cl, Br, TsO, MsO, or HSO4, and R1 is as defined above with a compound of Formula (20)
Rxe2x80x94CO2⊕xe2x8ax96Mxe2x80x83xe2x80x83(20)
xe2x80x83wherein R and M are as defined above with Compound (7) 
xe2x80x83in a solvent with removal of water to afford a compound of Formula (8).
A third aspect of the present invention is an improved process for the preparation of compound (13) 
which comprises:
Step (a) reacting a compound of Formula (11) with an acetal of Formula (15) 
xe2x80x83wherein R5 and R5a are independently the same or different and are, methyl, ethyl, or xe2x80x94(CH2)nxe2x80x94 wherein n is an integer of 2 to 4, and R is as defined above in a solvent in the presence of an acid followed by the addition of an aldehyde corresponding to the previous acetal in the presence of a base to afford a compound of Formula (14) 
xe2x80x83wherein R1 and R are as defined above;
Step (b) reacting a compound of Formula (14) in a nucleophilic solvent in the presence of an acid or optionally reaction with hydrogen in the presence of a catalyst and an acid in a solvent to afford the compound of Formula (13); and
Step (c) alternatively, reacting a compound of Formula (11) or (11a) in a non-nucleophilic solvent in the presence of an acid to afford a compound of Formula (13).
A fourth aspect of the present invention is a process for the preparation of a compound of Formula (11b) 
xe2x80x83wherein R1a is OH, xe2x80x94XR wherein
X is O,
S, or
Se, or R1a is 
xe2x80x83wherein R2 or R3 is independently
alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R2 and R3 together are
xe2x80x94(CH2)4xe2x80x94,
xe2x80x94(CH2)5xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)3xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)4xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)2xe2x80x94CH(R4))xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)3xe2x80x94CH(R4))xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH(R4)xe2x80x94
xe2x80x83wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N, and R is alkyl, aryl, arylalkyl, or heteroaryl which comprises:
Step (a) reacting a compound of Formula (10) 
xe2x80x83wherein R1 is as defined above with one mole of hydrogen in the presence of a catalyst in a solvent in the presence of an acid to afford compounds of Formula (18) and/or Formula (18a) 
xe2x80x83wherein R1 is as defined above; and
Step (b) reacting either a compound of Formula (18) or (18a) with hydrogen in the presence of a catalyst in a solvent in the presence of an acid to afford a compound of Formula (11b).
A fifth aspect of the present invention is a compound of Formula (6) 
wherein R is alkyl, aryl, arylalkyl, or heteroaryl, and
R1 is XR wherein
X is O,
S, or
Se, or R1 is 
xe2x80x83wherein R2 or R3 is independently
alkyl,
cycloalkyl,
arylalkyl, or
aryl or
R2 and R3 together are
xe2x80x94(CH2)4xe2x80x94,
xe2x80x94(CH2)5xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)3xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)4xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)2xe2x80x94CH(R4))xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)3xe2x80x94CH(R4))xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2CH2xe2x80x94,
xe2x80x83xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH(R4)xe2x80x94
xe2x80x83wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N and R is as defined above.
Particularly preferred, is a compound of Formula (6) wherein R is PhCH2xe2x80x94 or (CH3)3xe2x80x94Cxe2x80x94, and R1 is 
More particularly preferred, is a compound of Formula (6) wherein R is PhCH2xe2x80x94 and R1 is 
A sixth aspect of the present invention is a compound of Formula (8) 
wherein R1 is as defined above.
Particularly preferred is a compound of Formula (8) wherein R1 is 
A seventh aspect of the present invention is a compound of Formula (10) or a pharmaceutically acceptable salt thereof 
wherein R1 is as defined above.
Particularly preferred is a compound of Formula (10) wherein R1 is xe2x80x94O-tertiary butyl, xe2x80x94O-isopropyl, xe2x80x94O-ethyl, xe2x80x94O-methyl, 
xe2x80x94NMe2.
An eighth aspect of the present invention is the compound of Formula (12) 
A ninth aspect of the present invention is a compound of Formula (18) or a pharmaceutically acceptable salt thereof 
wherein R1 is as defined above.
Particularly preferred is a compound of Formula (18) wherein R1 is xe2x80x94O-tertiary butyl, xe2x80x94O-isopropyl, xe2x80x94O-ethyl, xe2x80x94O-methyl, 
or xe2x80x94NMe2.
A tenth aspect of the present invention is a compound of Formula (18a) or a pharmaceutically acceptable salt thereof 
wherein R1 is as defined above. Particularly preferred is a compound of Formula (18a) wherein R1 is xe2x80x94O-tertiary butyl, xe2x80x94O-isopropyl, xe2x80x94O-ethyl, xe2x80x94O-methyl, 
or xe2x80x94NMe2.
The term xe2x80x9calkyl xe2x80x9d means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
xe2x80x9cAlkoxy xe2x80x9d and xe2x80x9cthioalkoxy xe2x80x9d are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for xe2x80x9calkyl xe2x80x9d.
The term xe2x80x9ccycloalkyl xe2x80x9d means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
The term xe2x80x9caryl xe2x80x9d means an aromatic radical which is a phenyl group, a phenylalkyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano, 
as defined above for alkyl, xe2x80x94(CH2)n2-N(alkyl)2 wherein n2 is an integer of 1 to 5 and alkyl is defined above and 
as defined above for alkyl and n2.
The term xe2x80x9callyl xe2x80x9d means a hydrocarbon radical of 3 to 8 carbon atoms, containing a double bond between carbons 2 and 3, unsubstituted or substituted by 1 to 3 substituents on the carbons containing the double bond selected from alkyl or aryl as defined above, and includes, for example, propenyl, 2-butenyl, cinnamyl, and the like.
The term xe2x80x9carylalkyl xe2x80x9d means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above for example, benzyl, phenylethyl, 3-phenylpropyl, (4-chlorophenyl)methyl, and the like.
xe2x80x9cAlkali metal xe2x80x9d is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.
xe2x80x9cAlkaline-earth metal xe2x80x9d is a metal in Group IIA of the periodic table and includes, for example, calcium, barium, strontium, magnesium, and the like.
The term xe2x80x9cheteroaryl xe2x80x9d means a 5- and 6-membered heteroaromatic radical which may optionally be fused to a benzene ring containing 1 to 3 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, or 2- or 5-thiadiazolyl and the like optionally substituted by a substituent selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano, 
as defined above for alkyl, xe2x80x94(CH2)n2-N(alkyl)2 wherein n2 is an integer of 1 to 5, and alkyl is as defined above, and 
as defined above for alkyl and n2.
Pharmaceutically acceptable acid addition salts of the compounds of the present invention include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts, xe2x80x9d J. of Pharma. Sci., 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts, xe2x80x9d J. of Pharma Sci., 1977;66:1).
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Additionally, the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The following list contains abbreviations and acronyms used within the schemes and text:
The process of the present invention in its first aspect is a new, improved, economical, and commercially feasible method for the preparation of the compound of Formula (13) 
The process of the present invention in its first aspect is outlined in Scheme 1. Thus, a compound of Formula (1) wherein R is alkyl, aryl, arylalkyl, or heteroaryl is reacted with a compound of Formula (2) wherein R1 is xe2x80x94XR wherein
X is O,
S,
Se or R1 is 
xe2x80x83wherein R2 or R3 is independently
alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R2 and R3 together are
xe2x80x94(CH2)4xe2x80x94,
xe2x80x94(CH2)5xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)3xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)4xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)2xe2x80x94CH(R4))xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)3xe2x80x94CH(R4))xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH(R4)xe2x80x94
xe2x80x83wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N and R is as defined above in a solvent such as, for example, methyl tertiary butyl ether, and the like, to afford a compound of Formula (3) whereas R1 is as defined above. Preferably, the reaction is carried out with a compound of Formula (2) wherein R1xe2x80x94H is morpholine in methyl tertiary butyl ether.
A compound of Formula (3) is reacted with hydrogen in the presence of a catalyst such as, for example, Pt/C, Pd/C in the presence of an acid such as, for example, a strong acid, for example, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, and the like (optionally the reduction is carried out with Sponge Ni/NH4OH, metal hydrides, and the like, to afford the free base of a compound of Formula (4)) in a solvent such as, for example, methanol, ethanol, and the like to afford a compound of Formula (4) wherein Y is Cl, Br, TsO, MsO, or HSO4 and R1 is as defined above.
Preferably, the reaction is carried out in the presence of Pt/C, hydrochloric acid and hydrogen in methanol.
A compound of Formula (4) is reacted with a base such as, for example, sodium methoxide and the like in a solvent such as, for example, tetrahydrofuran, toluene, methyl tertiary butyl ether, and the like, and in an alcohol such as, for example, isopropanol, ethanol, methanol, and the like, to afford the free base followed by reaction with a compound of Formula (5) wherein R is as defined above in a solvent such as, for example, isopropanol, tetrahydrofuran, and the like to afford a compound of Formula (6) wherein R is as defined above. Optionally, the free base of a compound of Formula (4) may be reacted with a compound of Formula (5) to afford a compound of Formula (6). Preferably, the reaction is carried out with sodium methoxide in methyl tertiary butyl ether and methanol to afford the free base followed by reaction with phenylacetic in tetrahydrofuran.
A compound of Formula (6) is reacted with the compound of Formula (7) in a solvent such as, for example, a protic, an aprotic, a polar or a non-polar solvent, for example, tetrahydrofuran and the like with removal of water with the aid of a chemical drying agent such as, for example, molecular sieves and the like or with the aid of a Dean-Stark water trap or using azeotropic distillation with a suitable solvent such as, for example toluene and the like to afford a compound of Formula (8) wherein R1 is as defined above. Preferably, the reaction is carried out with activated 3A molecular sieves in tetrahydrofuran.
A compound of Formula (8) is reacted with a compound of Formula (9) wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum and R1 is as defined above in a solvent such as, for example, a nonreactive aprotic solvent, for example, tetrahydrofuran, toluene, and the like in the presence of a strong base such as, for example, n-butyllithium, lithium or potassium hexamethyldisilazide, lithium diisopropylamide, and the like to afford a compound of Formula (10) wherein R1 is as defined above. Preferably, the reaction is carried out with a compound of Formula (9) wherein M is sodium, the base is n-butyllithium and the solvent is tetrahydrofuran.
The carbonyls of a compound of Formula (10) in Scheme 1 are shown in the keto form. However, a compound of Formula (10) can undergo xe2x80x9cketo-enolxe2x80x9d tautomerism and thus can exist in several tautomeric forms which are encompassed within the present invention.
A compound of Formula (10) is treated with hydrogen in the presence of a catalyst such as, for example, a chiral non-racemic ruthenium (II)-diphosphine complex. For example, a ruthenium catalyst precursor such as [dichloro-(1,5-cyclooctadiene)]ruthenium (II) oligomer and chiral diphosphine ligand such as [(R)-(+)-2,2xe2x80x2-bis(diphenyl-phosphino)-1,1xe2x80x2-binaphthyl]. However, any chiral non-racemic ruthenium (II)/diphosphine combination may be employed in this reduction reaction. For example, ruthenium (II) catalyst precursors include [dibromo-(1,5-cyclooctadiene)]ruthenium (II) dimer, [bis-(2-methallyl)cycloocta-1,5-diene]ruthenium (II) complex and [dichloro(p-cymene)]ruthenium (II) dimer, and the like. Examples of effective chiral diphosphine ligands include 2,2xe2x80x2-bis(di-p-tolyl-phosphino)-1,1xe2x80x2-binaphthyl, 2-diphenyl-phosphinomethyl-4-diphenylphosphino-1-tert-butoxy-carbonylpyrrolidine, tricyclo[8 .2.2.24,7]hexadeca-4,6,10,12,13,15-hexaene-5,11-diyl-bis(diphenylphosphine) derivatives, 4,4xe2x80x2-bidibenzofuran-3,3xe2x80x2-diylbis(diphenylphosphine), 6,6xe2x80x2-dimethoxy[1,1xe2x80x2-biphenyl]-2,2xe2x80x2-diyl]bis-diphenylphosphine, [5,5xe2x80x2-dichloro-6,6xe2x80x2-dimethoxy[1,1xe2x80x2-biphenyl]-2,2xe2x80x2-diyl]-bis-diphenylphosphine, and 1,2-bis(2,5-dimethylphospholano) derivatives and the like in a solvent such as, for example, methanol, ethanol, isopropanol, and the like, optionally in the presence of a co-solvent, for example, dichloromethane, tetrahydrofuran, toluene and the like in the presence of an acid such as, for example, hydrochloric acid, hydrobromic acid, Dowex(copyright) ion exchange resin, and the like to afford a compound of Formula (11) or a compound of Formula (11a) wherein R1 is as defined above. Preferably, the reaction is carried out with dichloro(p-cymene) ruthenium (II) dimer and [(R)-(+)-5,5xe2x80x2-dichloro-6,6xe2x80x2-dimethoxy[1,1xe2x80x2-biphenyl]-2,2xe2x80x2-diyl]-bis-diphenylphosphine in methanol in the presence of hydrobromic acid.
A compound of Formula (11b) wherein R1a is wherein R1a is OH, xe2x80x94XR wherein
X is O,
S, or
Se, or R1a is 
xe2x80x83wherein R2 or R3 is independently
alkyl,
cycloalkyl,
arylalkyl, or
aryl, or
R2 and R3 together are
xe2x80x94(CH2)4xe2x80x94,
xe2x80x94(CH2)5xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)3xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94CH2)4xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)2xe2x80x94CH(R4))xe2x80x94,
xe2x80x94(CH(R4)xe2x80x94(CH2)3xe2x80x94CH(R4))xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2CH2xe2x80x94,
xe2x80x94CH(R4)xe2x80x94CH2xe2x80x94Axe2x80x94CH2xe2x80x94CH(R4)xe2x80x94
xe2x80x83wherein R4 is alkyl of from one to four carbon atoms, A is O, S, or N, and R is alkyl, aryl, arylalkyl, or heteroaryl is reacted with an acid such as, for example, p-toluenesulfonic acid, camphor-sulfonic acid, sulfuric acid, hydrogen chloride, and the like in a non-nucleophilic solvent such as, for example, toluene, acetonitrile, dichloromethane, methyl tertiary butyl ether, and the like, followed by reaction with a base, such as, for example, triethylamine, pyridine, diisopropylethylamine, and the like, and with an acylating agent, such as, for example, acetic anhydride, benzoyl chloride, benzyl chloroformate, and the like, in the presence of 4-dimethylaminopyridine to afford the compound of Formula (12). Preferably, the reaction is carried out in toluene in the presence of p-toluenesulfonic acid, followed by treatment with triethylamine, acetic anhydride, and 4-dimethylaminopyridine in toluene.
A compound of Formula (12) is reacted with HOxe2x80x94M in an alcohol of Formula (17) or (17b) wherein M is sodium, lithium, potassium, zinc, magnesium, copper, calcium, or aluminum, or with a compound of Formula (16) or (16b) wherein M is as defined above in an alcohol of Formula (17) or (17b) wherein aryl or allyl in a compound of Formula (16) or (16b) and (17) or (17b) is the same, in an optional cosolvent, such as, for example, a nonnucleophilic solvent, for example, acetone, tetrahydrofuran, 1,2-dimethoxyethane, and the like, followed by the addition of hydrogen in the presence of a catalyst, such as, for example, Pd(OH)2/C, Pd/C, Pd/Al2O3, and the like, in the presence of an acid, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like, to afford the compound of Formula (13). Preferably, the reaction is carried out with sodium hydroxide in benzyl alcohol followed by hydrogenation in the presence of Pd(OH)2/C and sulfuric acid.
The process of the present invention in its second aspect is outlined in Scheme 2. Thus, a compound of Formula (4), prepared as described in Scheme 1, is reacted with a compound of Formula (20) wherein R and M are as defined above and a compound of Formula (7) with removal of water with the aid of a chemical drying agent such as, for example, molecular sieves and the like or with the aid of a Dean-Stark water trap or using azeotropic distillation with a suitable solvent such as, for example tetrahydrofuran, toluene, and the like, to afford a compound of Formula (8) wherein R1 is as defined above. Preferably, the reaction is carried out with a compound of Formula (20) wherein R is PhCH2 and M is sodium in the presence of activated 3A molecular seives in tetrahydrofuran.
The process of the present invention in its third aspect is outlined in Scheme 3. Thus, a compound of Formula (11) is reacted with an acetal of Formula (15) wherein R5 and R5a are independently the same or different and are, methyl, ethyl, or xe2x80x94(CH2)nxe2x80x94 wherein n is an integer of 2 to 4, and R is as defined above in the presence of an acid such as, for example, hydrochloric acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid and the like in a solvent such as, for example, toluene, dichloromethane, methyl tertiary butyl ether, and the like, followed by the addition of an aldehyde corresponding to the previous acetal of Formula (15) in the presence of a strong base such as, for example, a non-nucleophilic base, for example, potassium tertiary butoxide, potassium bis(trimethylsilyl) amide, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like, to afford a compound of Formula (14) wherein R1 and R are as defined above. Preferably, the reaction is carried out with benzaldehyde dimethyl acetal in toluene in the presence of p-toluenesulfonic acid followed by the addition of benzaldehyde and potassium tertiary butoxide in tetrahydrofuran.
A compound of Formula (14) is reacted with hydrogen in the presence of a catalyst such as, for example, palladium on carbon or platinum on carbon and the like in the presence of an acid such as, for example, hydrochloric acid and the like in a solvent such as, for example, toluene, tetrahydrofuran, methyl tertiary butyl ether, ethyl acetate, and the like, and an alcohol, such as, for example, methanol, ethanol, and the like, to afford a compound of Formula (13). Preferably, the reaction is carried out in toluene in the presence of platinum on carbon in the presence of methanol in the presence of hydrochloric acid.
Optionally, a compound of Formula (14) is reacted with an acid such as, for example, hydrochloric acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, and the like, in a solvent such as, for example, toluene, dichloromethane, methyl tertiary butyl ether, and the like to afford the compound of Formula (13). Preferably, the reaction is carried out in methylene chloride in the presence of p-toluenesulfonic acid.
Alternatively, a compound of Formula (11) is reacted with an acid, such as, for example, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, and the like, in a non-nucleophilic solvent, such as, for example, toluene, acetonitrile, methyl tertiary butyl ether, tetrahydrofuran, and the like, to afford a compound of Formula (13). Preferably, the reaction is carried out in toluene in the presence of p-toluenesulfonic acid.
The process of the present invention in its fourth aspect is outlined in Scheme 4. Thus, a compound of Formula (10) wherein R1 is as defined above is reacted with one molar equivalent of hydrogen in the presence of a catalyst using the methodology described above for the conversion of a compound of Formula (10) to a compound of Formula (11) to afford either a compound of Formula (18) or Formula (18a) wherein R1 is as defined above or a mixture thereof. A mixture of compounds of Formula (18) and (18a) may be separated using conventional methodology, such as, for example, chromatography and the like. Preferably, a mixture of compounds of Formula (18) and (18a) is separated using HPLC.
A compound of Formula (18) or (18a) or a mixture thereof is reacted with hydrogen in the presence of a catalyst as described above for preparing a compound of Formula (11) to afford a compound of Formula (11b) wherein R1a is as defined above. Preferably, the reaction is carried out using at least one molar equivalent of hydrogen.
The compound of Formula (13) can be converted to atorvastatin calcium (19) using the procedures disclosed in U.S. Pat. Nos. 5,273,995 and 5,969,156.